Enantio- and diastereoselective michael reaction of 1,3-dicarbonyl compounds to nitroolefins catalyzed by a bifunctional thiourea

Article abstract of DOI:10.1021/ja044370p

We synthesized a new class of bifunctional catalysts bearing a thiourea moiety and an amino group on a chiral scaffold. Among them, thiourea 1e bearing 3,5-bis(trifluoromethyl)benzene and dimethylamino groups was revealed to be highly efficient for the as

Full text of DOI:10.1021/ja044370p

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Enantio- and Diastereoselective Michael Reaction of
1,3-Dicarbonyl Compounds to Nitroolefins Catalyzed by a
Bifunctional Thiourea
Tomotaka Okino, Yasutaka Hoashi, Tomihiro Furukawa, Xuenong Xu, and
Yoshiji Takemoto*
Contribution from the Graduate School of Pharmaceutical Sciences, Kyoto UniVersity,
Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Received September 16, 2004; E-mail: takemoto@pharm.kyoto-u.ac.jp
Abstract: We synthesized a new class of bifunctional catalysts bearing a thiourea moiety and an amino
group on a chiral scaffold. Among them, thiourea 1e bearing 3,5-bis(trifluoromethyl)benzene and
dimethylamino groups was revealed to be highly efficient for the asymmetric Michael reaction of
1,3-dicarbonyl compounds to nitroolefins. Furthermore, we have developed a new synthetic route for
(R)-(-)-baclofen and a chiral quaternary carbon center with high enantioselectivity by Michael reaction. In
these reactions, we assumed that a thiourea moiety and an amino group of the catalyst activates a nitroolefin
and a 1,3-dicarbonyl compound, respectively, to afford the Michael adduct with high enantio- and
diastereoselectivity.
Introduction
Jacobsen et al. found that chiral urea derivatives catalyzed the
Strecker reaction, Mannich reaction, hydrophosphonylation of
Urea and thiourea derivatives have been intensively inves-
tigated in the area of molecular recognition because of their
strong hydrogen bonding activity.1 They can be used to recog-
nize carboxylic acid,1a sulfonic acid,1b nitrate,1c etc., through
multihydrogen bondings. Recently, several groups reported that
urea and thiourea not only recognized organic compounds but
also activated them as an acid catalyst.2-4 Curran et al. reported
that addition of a urea derivative improved diastereoselectivity
of allylation of R-bromosulfoxide with allyltributylstannane.2b
Schreiner investigated the effect of urea derivatives on reactivity
and selectivity of Diels-Alder reaction of enones with
cyclopentadiene.2d,e Concerning enantioselective reactions,3,4
imines, and Pictet-Spengler reaction, affording the products
with high enantiomeric excess.4a-i Nagasawa et al. reported that
their chiral urea derivatives promoted Michael reaction of
pyrrolidine to R,â-unsaturated γ-lactone with low to moderate
ee.4j They also found that bis-thiourea catalyzed the Baylis-
Hillman reaction with up to 90% ee.4k Although both research
groups used urea derivatives as a simple acid, the activity of
ureas as acids is rather weaker than that of metallic Lewis acids.
Therefore, application of urea derivatives to enantioselective
reactions seems to be limited.2g
Michael reaction of nitroolefins represents a convenient access
to nitroalkanes that are versatile intermediates in organic
synthesis.5 The nitro functionality can be easily transformed into
amine,6 nitrile oxide,7 ketone or carboxylic acid,8 hydrogen,9
etc., providing a wide range of synthetically interesting com-
pounds. Although the catalytic asymmetric versions of this
reaction were achieved, most required metal catalysts or strict
reaction conditions.10-14 Recently, L-proline derivatives have
been reported to afford enantiomerically enriched Michael
adducts in good yield.15 To achieve catalytic enantioselective
Michael reaction into nitroolefins with thioureas, we designed
(1) (a) Kelly, T. R.; Kim, M. H. J. Am. Chem. Soc. 1994, 116, 7072-7080.
(b) Wilcox, C. S.; Kim, E.; Romano, D.; Kuo, L. H.; Burt, A. L.; Curran,
D. P. Tetrahedron 1995, 51, 621-634. (c) Linton, B. R.; Goodman, M.
S.; Hamilton, A. D. Chem.-Eur. J. 2000, 6, 2449-2455. (d) Etter, M. C.;
Urban˜czyk-Lipkowska, Z.; Zia-Ebrahimi, M.; Panunto, T. W. J. Am. Chem.
Soc. 1990, 112, 8415-8426.
(2) (a) Okino, T.; Hoashi, Y.; Takemoto, Y. Tetrahedron Lett. 2003, 44, 2817-
2821. (b) Curran, D. P.; Kuo, L. H. J. Org. Chem. 1994, 59, 3259-3261.
(c) Curran, D. P.; Kuo, L. H. Tetrahedron Lett. 1995, 36, 6647-6650. (d)
Schreiner, P. R.; Wittkopp, A. Org. Lett. 2002, 4, 217-220. (e) Wittkopp,
A.; Schreiner, P. R. Chem.-Eur. J. 2003, 9, 407-414. (f) Schreiner, P. R.
Chem. Soc. ReV. 2003, 32, 289-296. (g) Maher, D. J.; Connon, S. J.
Tetrahedron Lett. 2004, 45, 1301-1305.
(3) (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125,
12672-12673. (b) Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y.
Org. Lett. 2004, 6, 625-627.
(4) (a) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901-
4902. (b) Sigman, M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem., Int.
Ed. 2000, 39, 1279-1281. (c) Vachal, P.; Jacobsen, E. N. J. Am. Chem.
Soc. 2002, 124, 10012-10014. (d) Vachal, P.; Jacobsen, E. N. Org. Lett.
2000, 2, 867-870. (e) Su, J. T.; Vachal, P.; Jacobsen, E. N. AdV. Synth.
Catal. 2001, 343, 197-200. (f) Wenzel, A. G.; Jacobsen, E. N. J. Am.
Chem. Soc. 2002, 124, 12964-12965. (g) Wenzel, A. G.; Lalonde, M. P.;
Jacobsen, E. N. Synlett 2003, 1919-1922. (h) Joly, G. D.; Jacobsen, E. N.
J. Am. Chem. Soc. 2004, 126, 4102-4103. (i) Taylor, M. S.; Jacobsen, E.
N. J. Am. Chem. Soc. 2004, 126, 10558-10559. (j) Sohtome, Y.; Tanatani,
A.; Hashimoto, Y.; Nagasawa, K. Chem. Pharm. Bull. 2004, 52, 477-
480. (k) Sohtome, Y.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K.
Tetrahedron Lett. 2004, 45, 5589-5592.
(5) For a review, see: Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org.
Chem. 2002, 1877-1894.
(6) (a) Beck, A. K.; Seebach, D. Chem. Ber. 1991, 124, 2897-2911. (b) Maeri,
R. E.; Heinzer, J.; Seebach, D. Liebigs Ann. 1995, 1193-1215. (c) Poupart,
M. A.; Fazal, G.; Goulet, S.; Mar, L. T. J. Org. Chem. 1999, 64, 1356-
1361. (d) Barrett, A. G. M.; Spilling, C. D. Tetrahedron Lett. 1988, 29,
5733-5734. (e) Lloyd, D. H.; Nichols, D. E. J. Org. Chem. 1986, 51,
4294-4295.
(7) Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82, 5339-5342.
(8) Pinnick, H. W. Org. React. 1990, 38, 655-792.
(9) Ono, N.; Miyake, H.; Kamimura, A.; Hamamoto, I.; Tamura, R.; Kaji, A.
Tetrahedron 1985, 41, 4013-4023.
(10) (a) Hayashi, T. Synlett 2001, 879-887. (b) Hayashi, T.; Senda, T.;
Ogasawara, M. J. Am. Chem. Soc. 2000, 122, 10716-10717.
9
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J. AM. CHEM. SOC. 2005, 127, 119-125
119

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A R T I C L E S
Okino et al.
Figure 2. Synthesis of thiourea catalysts.
Table 1. Michael Reaction of 2a with Various Catalystsa
Figure 1. Multifunctional organocatalysts.
new chiral bifunctional organocatalysts2f,16 (Figure 1) that have
both a thiourea moiety and an amino group on a chiral scaffold.
These bifunctional catalysts would be able to activate both
nitroolefins and nucleophiles simultaneously and could control
the approach of nucleophiles to nitroolefins. On the basis of
this concept, we have recently reported that novel bifunctional
catalysts realized Michael reaction of 1,3-dicarbonyl compounds
to nitroolefins with high enantioselectivity up to 93% ee.3a In
this article, we investigated the structure-activity relationship
of thiourea catalysts in the Michael reaction and also the
adaptation of R-substituted â-ketoesters to the reaction to con-
struct contiguous stereogenetic centers containing an asymmetric
quaternary carbon. In addition, a plausible reaction mechanism
is proposed from these results.
entry
additive
time (h)
% yieldb
% eec,d
1
2
3
4
5
6
7
8
TEA
DBU
TEA + 1a
24
3
17
13
57
38
43
52
86
69
88
78
58
72
88
76
38
87
14
-
-
24
48
48
48
24
48
48
48
48
24
48
48
48
24
24
-
1b
1c
1d
1e
1f
1g
1h
1i
-
-
64
93
74
83
84
80
72
77
87
89
91
35
9
10
11
12
13
14
15
16
17
1j
1k
1l
1m
1n
1o
Results and Discussion
Synthesis and Activity of Catalysts. We first synthesized
various thiourea derivatives 1a-n to examine the effects of (1)
the diamine moiety (cyclic or acyclic, n, R1), (2) a functional
group of the aromatic ring (Y), and (3) substituents on the amino
group (R2, R3) on the reactivity and selectivity of the reaction
(Figure 2). These catalysts could be prepared simply by
condensation of isocyanates/isothiocyanates with 1 equiv of
amines. Furthermore, we synthesized urea 1o, whose pKa would
be larger than that of the corresponding thiourea 1e.17 We then
carried out Michael reaction of â-nitrostyrene 2a with 2 equiv
of diethyl malonate 3a in toluene with 10 mol % of catalysts
(Table 1 and Figure 3). The reaction in the presence of TEA
a The reaction was conducted with 2a (1 equiv), 3a (2 equiv), and toluene
in the presence of various additives (10 mol %) at room temperature.
b Isolated yield. c Enantiomeric excess was determined by HPLC analysis
of 4a using a chiral column. d Absolute configuration was determined by
comparing the specific rotation of 4a with that of literature data.12b
(11) (a) Duursma, A.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2003,
125, 3700-3701. (b) Duursma, A.; Minnaard, A. J.; Feringa, B. L.
Tetrahedron 2002, 58, 5773-5778. (c) Alexakis, A.; Benhaim, C.; Rosset,
S.; Humam, M. J. Am. Chem. Soc. 2002, 124, 5262-5263. (d) Rimkus,
A.; Sewald, N. Org. Lett. 2003, 5, 79-80. (e) Luchaco-Cullis, C. A.;
Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 8192-8193. (f) Mampreian,
D. M.; Hoveyda, A. H. Org. Lett. 2004, 6, 2829-2832. (g) Choi, H.; Hua,
Z.; Ojima, I. Org. Lett. 2004, 6, 2689-2691. (h) Watanabe, M.; Ikagawa,
A.; Wang, H.; Murata, K.; Ikariya, T. J. Am. Chem. Soc. 2004, 126, 11148-
11149.
(12) (a) Barnes, D. M.; Ji, J.; Fickes, M. G.; Fitzgerald, M. A.; King, S. A.;
Morton, H. E.; Plagge, F. A.; Preskill, M.; Wagaw, S. H.; Wittenberger, S.
J.; Zhang, J. J. Am. Chem. Soc. 2002, 124, 13097-13105. (b) Ji, J.; Barnes,
D. M.; Zhang, J.; King, S. A.; Wittenberger, S. J.; Morton, H. E. J. Am.
Chem. Soc. 1999, 121, 10215-10216.
(13) Brunner, H.; Kimel, B. Monatsh. Chem. 1996, 127, 1063-1072.
(14) Very recently, Deng et al. reported enantioselective Michael reaction of
nitroolefins with malonates catalyzed by cinchona alkaloid derivatives. Li,
H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126, 9906-
9907.
(15) (a) Andrey, O.; Alexakis, A.; Bernardinelli, G. Org. Lett. 2003, 5, 2559-
2561. (b) Enders, D.; Seki, A. Synlett 2002, 26-28. (c) List, B.; Pojarliev,
P.; Martin, H. J. Org. Lett. 2001, 3, 2423-2425. (d) Mase, N.; Thayumana-
van, R.; Tanaka, F.; Barbas, C. F., III. Org. Lett. 2004, 6, 2527-2530. (e)
Ishii, T.; Fujioka, S.; Sekiguchi, Y.; Kotsuki, H. J. Am. Chem. Soc. 2004,
126, 9558-9559.
Figure 3. Structure of catalysts.
(16) For a review of bifunctional catalysts, see: (a) Ma, J.; Cahard, D. Angew.
Chem., Int. Ed. 2004, 43, 4566-4583. (b) Gro¨ger, H. Chem.-Eur. J. 2001,
7, 5246-5251. (c) Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int.
Ed. Engl. 1997, 36, 1236-1256.
(10 mol %) provided the desired Michael adduct 4a in only
17% yield (entry 1). Replacement of the base with a strong base
DBU did not improve the chemical yield (13%, entry 2). The
(17) Mitchell, J. M.; Finney, N. S. Tetrahedron Lett. 2000, 41, 8431-8434.
9
120 J. AM. CHEM. SOC. VOL. 127, NO. 1, 2005

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Michael Reaction of 1,3-Dicarbonyl Compounds
A R T I C L E S
low yield of 4a was attributed to decomposition of â-nitrostyrene
2a by these bases. To activate â-nitrostyrene with something
other than a base, thiourea 1a was added to the reaction mixture.
When 1a and TEA coexist in the reaction mixture, Michael
reaction was accelerated and 4a was obtained in 57% yield
(entry 3). In contrast to our expectation of higher activity, achiral
bifunctional organocatalysts 1b and 1c gave almost the same
results as that of entry 3 (entries 4 and 5). In these cases, the
two functional groups might not be fixed in proper positions
because of the conformational flexibility. Indeed, although chiral
catalyst 1d, bearing 1,2-diphenylethylenediamine as the scaffold,
gave 4a with 64% ee, catalyst 1e, bearing a rigid chair-form
structure, afforded 4a in good yield with 93% ee (entries 6 and
7). The absolute configuration of 4a was determined to be R
by comparing the specific rotation of 4a with that of literature
data.12 We next examined the catalytic activity of several cata-
lysts 1f-i, which had differernt substituents (Y ) CF3, CN,
OMe, H in Figure 2) on the meta position of the aromatic rings.
Although these catalysts showed lower catalytic activity than
1e, similar results in terms of chemical yield and ee were
obtained except in the case of 1f possessing an electron-donating
group (entries 8-11). Similarly, the position of CF3 groups on
the aromatic ring had a marginal effect on the chemical yield
and enantioselectivity of 4a (entries 10, 12, and 13). Concerning
the number of trifluoromethyl groups on the aromatic ring of
the catalyst (entries 7, 10, and 11, 1e, 1h, and 1i), the catalyst
1e, bearing two CF3 groups, showed the highest catalytic activity
due to enhancement of the acidity of thiourea N-H groups.
When a bulkier alkyl group (R2) was introduced to the catalyst,
the chemical yield of 4a decreased without affecting the ee of
4a (entries 14 and 15). It implied that steric hindrance of the
catalyst did not relate to the facial selectivity of nitroolefin 2a,
but disturbed the approach of the nucleophile to 2a. In general,
the pKa of the N-H groups of urea derivatives is smaller
than that of the corresponding thiourea. Though we specu-
lated that urea 1n would show lower activity than 1e, the
catalytic activity of 1n was almost the same as that of 1e (entry
16). The unsatisfactory result with amide 1o18 indicated the
importance of cooperative effect of two N-H groups in the
catalyst (entry 17).
Figure 4. X-ray analysis of rac-1e.
Table 2. Enantioselective Michael Reaction of 2a with Malonates
3b-o in the Presence of 1ea
entry
3
R1
R2
time (h)
yieldb (%)
eec,d (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
OMe
H
H
H
H
0.25
H
9
48
48
1
85
24
36
28
1
48
24
1
48
48
89
70
86
88
-
OiPr
OtBu
Me
trace
80
89e
NCCH2CN
OCMe2O
OMe
OMe
OMe
OEt
OEt
OMe
OEt
25e
88
46f
93e
94
Me
82
89
86
81
72
>99
nr
OMe
OMs
NHBoc
NHAc
Cl
79e
82e
33
89e
-
Br
Ph
OMe
trace
-
a The reaction was conducted with 2a (1 equiv), nucleophiles (2 equiv),
and toluene in the presence of 1e (10 mol %) at room temperature. b Isolated
yield. c Enantiomeric excess was determined by HPLC analysis of 4 using
a chiral column. d Absolute configuration was determined by comparing
the specific rotation of 4 with that of literature data.12b e Absolute
configuration was not determined. f Enantiomeric excess was determined
after conversion to 4a (see Supporting Information).
Although it is known that the solubility of ureas and thioureas
in nonpolar solvents is low because of strong intermolecular
hydrogen bonding, introduction of an amino group in the
thiourea would induce formation of intramolecular hydrogen
bonding between the amino group (NR2) and the N-H groups
of the thiourea, leading to increasing solubility to nonpolar
solvents.1d Indeed, bifunctional thioureas 1d-n became soluble
in toluene. Analysis of the X-ray crystallographic structure of
racemic thiourea 1e would support the intramolecular hydrogen
bonding between the amino group and the thiourea N-H group
(H-N ) 2.70 Å, Figure 4). In addition, the X-ray crystal-
lography of 1e would indicate that amino groups and thiourea
N-H orient to the same direction. If thiourea and the amino
group interact with nitroolefins and nucleophiles, respectively,
nucleophiles can approach nitroolefins in an ideal way. This
hypothesis agrees with the experimental result in Table 1, and
it encouraged us to employ the catalyst 1e to Michael reaction
of various nucleophiles 3b-o to nitroolefin 2a.
reactions with a series of malonates 3b-o using the best catalyst
1e (Table 2). The size of ester groups of malonates had a
marginal effect on the selectivity of Michael adducts, but the
large ester groups such as tert-butyl ester decreased reactivity
of the malonates (entries 1-3). Acetylacetone 3e, whose
R-proton was more acidic than that of malonates, reacted with
â-nitrostyrene for 1 h to afford 80% yield of Michael adduct
4e with 89% ee (entry 4). In contrast, malononitrile 3f and
Meldrum’s acid 3g gave the corresponding adducts 4f and 4g
in 85% yield and 88% yield, respectively, but the selectivity of
both adducts was low (entries 5 and 6). The results suggest that
the six-membered cyclic enol form of 1,3-dicarbonyl compounds
might be important for the good enantioselectivity. If R-sub-
stituted malonates can be employed as a nucleophile in the
Michael reaction, various products bearing a quaternary carbon
Michael Reaction with Symmetric 1,3-Dicarbonyl Com-
pounds. We next examined the scope of this class of Michael
(18) Bordwell, F. G.; Ji, G. J. Am. Chem. Soc. 1991, 113, 8398-8401.
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J. AM. CHEM. SOC. VOL. 127, NO. 1, 2005 121

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A R T I C L E S
Okino et al.
Table 3. Enantio- and Diastereoselective Michael Reaction of 2a
with Ketoesters 5a-k in the Presence of 1e
center would be obtained. Barnes et al. had already carried out
such reactions with magnesium catalysts, but the products were
obtained only in low to moderate selectivity.12b However,
R-methyl malonate 3h smoothly reacted with â-nitrostyrene in
the presence of 1e to provide Michael adduct 4h in 82% yield
with 93% ee (entry 7). The R-hydroxymalonate derivatives 3i
and 3j also gave Michael adducts 4i and 4j in high yield with
good to excellent selectivity (entries 8 and 9). In the reactions
with malonates bearing nitrogen substituents on the R-position,
the selectivity of the products depended on the protecting groups
of the nitrogen (entries 10 and 11). In the case of N-Boc
R-aminomalonate 3k, the reaction afforded the product 4k in
81% yield with 82% ee. Similarly, the reactivity of the
halogenated malonates 3m and 3n depended on acidity of the
malonates. Although R-chloromalonate 3m provided the desired
product 4m quantitatively with 89% ee, the same reaction with
R-bromomalonate 3n did not proceed (entries 12 and 13).
Unfortunately, the reaction with R-phenylmalonate 3o gave only
a trace amount of 4o. The absolute configurations of 4b, 4c, 4i,
and 4l were determined by comparing their specific rotations
with those of literature data12b to reveal that all products had
the same R configuration. These results would indicate that the
reactions listed in Table 2 proceed through the same mechanism
and also that adequate acidity of malonate is crucial for good
chemical yield but not high enantioselectivity. We succeeded
in highly enantioselective Michael reaction of â-nitrostyrene
2a with several malonates to construct a quaternary carbon
center.
Application to Enantio-/Diastereoselective Michael Reac-
tion. Having succeeded in the Michael reaction of â-nitrostyrene
with symmetric 1,3-dicarbonyl compounds such as malonate,
we next carried out the Michael reaction of 2a with prochiral
1,3-dicarbonyl compounds (Table 3). We first investigated the
addition of R-unsubstituted â-ketoester 5a,b to â-nitrostyrene
2a. When ethyl aceoacetate 5a (2 equiv) and â-nitrostyrene were
combined in toluene in the presence of 10 mol % of catalyst 1e
at room temperature, the Michael addition completed within
30 min, giving the desired product 6a in 91% yield. Although
the dr of 6a was low (55/45), the enantioselectivity was high
(entry 1). The absolute configuration of the C3 position of 6a
was determined to be R by comparing the retention time of chiral
HPLC analysis of 6a with that of literature data.12b This result
indicated that the reaction of ketoester 5a with nitroolefin 2a
would proceed in the same way as that of malonates. The
â-ketoester 5b bearing aryl groups could be used as a nucleo-
phile to afford the adduct 6b in good yield with high enantio-
selectivity (entry 2). We next investigated the diastereo- and
enantioselective Michael addition by using R-substituted â-ke-
toester 5c-j, which generates a configurationally stable qua-
ternary stereocenter. To the best of our knowledge, there is no
report of Michael reaction of ketoesters to nitroolefins construct-
ing a stereogenic quaternary carbon center with high diastereo-
and enantioselectivity. We screened a variety of nucleophiles,
and the representative results are listed in Table 3, entries 3-10.
The same reaction of ethyl 2-methylacetoacetate 5c with 2a in
the presence of 10 mol % of 1e completed within 6 h to provide
the desired product 6c in 89% yield (entry 3). Although the
enantioselectivity of major product 6c was still high (91% ee),
the ratio of two diastereomers was moderate (78/22). The use
of 5d bearing a bulky alkyl group led to a decrease of the
a Isolated yield. b Determined by 1H NMR. c Relative configuration was
determined by 1H NMR(NOE) or X-ray analysis. d Enantiomeric excess
was determined by HPLC analysis of 6 using a chiral column. e Absolute
configuration was determined by comparing the retention time of HPLC of
6 with that of literature data.12b
diastereoselectivity, but the enantioselectivity was maintained
at a high level (entry 4). Therefore, we turned our attention to
cyclic ketoester 5e-j as a reacting partner (entries 5-10). It
was revealed that 2-methoxycarbonycyclopentanone 5e added
to 2a to provide adduct 6e with 93/7 diastereoselectivity and
93% ee at -50 °C. The scope of the reaction proved to be quite
broad with respect to ring size of the nucleophile: five- to seven-
membered substrates as well as bicyclic compounds could be
employed to give the Michael adducts 6e-i with good to high
stereoselectivity with the exception of entry 8.
Furthermore, the reaction was applied to cyclic 1,3-diketone
5j to give 6j in 94% yield with good stereoselectivity (93/7 dr,
81% ee). The relative configurations of 6e and 6j were
1
determined by comparing the H NMR spectrum with that of
literature data,19 and those of 6f and 6i were determined by
X-ray analysis. The relative configurations of 6c and 6g were
determined by their NOE analysis of cyclic nitrones, which were
transformed from 6c and 6g. The configuration of the remaining
adducts was presumed from these results. It should be noted
that acyclic 1,3-ketoesters 5c,d afforded the major isomers 6c,d
(19) Deutsch, J.; Niclas, H.-J.; Ramm, M. J. Prakt. Chem. 1995, 337, 23-28.
9
122 J. AM. CHEM. SOC. VOL. 127, NO. 1, 2005